Novel process for the preparation of an 11, 18-oxygenated steroid and products resulting therefrom



United States Patent ()fihce 3,037,021 Patented May 29, 1962 This invention relates to a novel process for the preparation of an 11,18-oxygenated steroid. It more particularly relates to a process for producing the 18,11-lactone of 1lfi-hydroxy-Mpregnene-B,20-dione-18-oic acid of the formula:

starting from 3u-acetoxy-18,20/3-0Xido-5fl-pregnane-llone, which itself is derived from a derivative of the bile acid series, thereby providing a passage from this series to aldosterone.

The present invention provides a method for the direct preparation, beginning with the same starting material as in the copending application, of an important but more advanced intermediate in the synthesis of the hormone in question, i.e. aldosterone. This intermediate is the 18,11-lactone of 1lfi-hydroXy-A -pregnene-3,20-dione-18-oic acid, described by I. Schmidlin et al., Exp-en, 11, 365 (1955), and by E. Vischer et al., Expen, 12, 50 (1956), but obtained in another, non-industrial manner.

It is therefore an object of this invention to provide a process for producing the 18,11-lactone of llp-hydroxy- A -pregnene-3,20-dine-18-0ic acid.

A further object of the invention is the production of the novel intermediate compounds:

The 3m-hydroxy-5 8-pregnane-l1,20-dione-l8-oic acid and its hydroxy lactone isomer.

The 18,11-lactone of 30,113,20,3-trihydroxy-5fl-pregnane-lS-oic acid,

5 The 18,1l-lactone of 11fl-hydroxy-5fi-pregnane-3,20-dione-l8-oic acid,

The 18,11-lactone of 4 f-bromo-lI S-hydroXy-SB-pregmane-3,20-dione-18-oic acid.

These and other objects of the invention will become 10 apparent as the description thereof proceeds.

The process for the preparation of the 18,11-1actonc of 11B hYdIOXY-A PIGgHCHC-S,20-dl0n18-Olc acid and the sequence of reactions are summarized in the sche- 15 matic flow sheet of Table I.

TABLE I HO- H0 IIB III O A) A0 I 1 HO- O H H HA IV 2 H Br These reactions consist essentially of:

(a) Oxidizing, with subsequent saponification, 3a-a06- toxy-l8,20-B-oxido-SB-pregnane-ll-one, I, in such a manner as to obtain the 3a-hydroxy-5B-pregnane-11,20-dione- 18-oic acid, IIA, which is conveniently isolated in the form of the hydroxy lactone isomer IIB, 20fi,l8-lactone of 3a,200t,20}3, trihydroxy-SB-pregnane-l1-one-18-oicacid.

(b) Transforming the hydroxy lactone IIB thus obtained by reduction into the 18,11-lactone of 3a,11,8,20fltrihydroxy-SB-pregnane-l8-oic acid, III,

(e) Oxidizing the hydroxyl groups in the 3- and 20- positions of the 18,1l-lactone of 3a,l1/3,2OB-trihydroxy- 3-pregnane-18-oic acid, III, which furnishes the 18,11- lactone of 11fl-hydr0xy-5/3-pregnane-3,20-dione-l8-oic acid, IV,

(d) Substituting the last compound with bromine in the 4-position and (e) Then dehydrobrominating the brominated derivative V, which leads to the desired 18,11-lactone of 11/9- hydroxy-N-pregnene-B,ZO-dione-18-oic acid, VI.

Within the scope of this general definition of the process, the various stages which constitute the invention may advantageously be executed in the following manner:

The oxidation of 3aacetoxy-18,20,3-oxido-55-pregnane ll-one is effected with a sulfochromic mixture, i.e., a mixture of sulfuric acid and chromic acid anhydride in the presence of an inert organic solvent such as acetic acid, followed by a treatment with alkali metal hydroxides. Then in the second stage, an alkali metal borohydride in the presence of an inert organic solvent such as ethanol is used as the reducing agent at reflux temperatures to transform the hydroxy lactone 1113 into the 18,11-lactone of 3a,1-lfi,20 8-trihydroxy-5B-pregnane-18- oic acid, III. Then Compound III is oxidized with the aid of chromic acid anhydride in solution in acetic acid or with a sulfochromic mixture in the presence of inert organic solvents such as methylene chloride and acetic acid. The following stage of the process, that is the introduction of the bromine into the 4-position of Compound IV, is carried out in the presence of an inert organic solvent such as dimethyl formamide with the aid of bromine in acetic acid. The final dehydrobromination is effected by means of a mixture of lithium bromide and lithium carbonate in the presence of an inert organic solvent such as dimethyl formamide at reflux temperatures.

The starting material for the invention, 3a-acetoxy- 18,20B-oxido-5fl-pregnane-1l-one, I, may be prepared by oxidizing the 3-monoacetate of 5/3-pregnane-3a,2018-dio1- ll-one by lead tetraacetate while heating to reflux in benzene, pouring the reaction mixture in an aqueous solution of sodium iodide, adding to the mixture sodium hyposulfite until the mixture is decolorized, isolating the raw oxidation product and purifying this last by chromatography on alumina.

The following examples are given to make the invention better understood and enable persons skilled in the art to better practice the invention and is not intended to be limitative. The melting points are instantaneous melting points determined on a Kofler block. The temperatures are indicated in degrees centigrade.

Example I PREPARATION OF 3a-ACETOXY-18,20fi-OXIDO-55- PRE GNANE-ll-ONE 5 grams of the 3-monoacetate of 5fl-pregnane-3a,20fldiol-ll-one, M.P. 204 C. were introduced into 200 cc. of benzene. 10 cc. of solvent were distilled off, 10 grams of lead tetraacetate were added and the mixture was refluxed for 16 hours. It was poured into 200 cc. of water containing 10 grams of sodium iodide and solid sodium hyposulfite was added until the mixture was decolorized. The mixture was decanted and extracted with ether. The ether extracts were separated, combined, washed with water, with sodium bicarbonate, dried over magneesium sulfate and evaporated to dryness under vacuum. 6 grams of a resin were recovered which were chromatographed on 150 grams of neutral alumina. Elution was effected with petroleum ether containing 2% of methylene chloride. There was obtained 3.31 grams of a resin which on crystallization from petroleum ether furnished 1.42 grams of 3u-acetoxy-18,20fl-oxido-5fi-pregnane-ll-one, having a melting point of 168 C. and a specific rotation [a] =+67i5(CI-ICl The product which has not yet been described is present in the form of small, colorless crystals, insoluble in water, soluble in alcohol, ether, acetone, benzene and chloroform, poorly soluble in petroleum ether.

Analysis.C H O molecular weight=374.50. Calculated: C, 73.76%; H, 9.15%; O, 17.09%. Found: C, 73.8%; H, 9.2; O, 17.5%.

Example II PREPARATION OF THE 18,11-LACTONE 0F llfi-HY- DROXY-N-PREGNENE-B,ZO-DIONE-IS'OIC-ACID, VI

(a) Hydroxylactone IIB.1 gm. of 3a-acetoxy-l8,2(l,B- oxido-Sfl-pregnane-ll-one, I, obtained by oxidation of 3u-acetoxy-2OB-hydroxy-Sfl-pregnane-1l-one with lead tetra-acetate according to the process described above, was dissolved in 10 cc. acetic acid. To this solution of Compound I, 3.2 cc. of 24% aqueous sulfochromic solution (containing 24 gm. chromic acid anhydride and 37 gm. sulfuric acid per cc. of solution) were added while agitating. The reaction mixture was agitated for two hours at room temperature. Thereafter, it was poured into water, and the aqueous mixture was extracted with chloroform containing 25% ethanol. The extract solutions were washed with sodium hydroxide and with water. The alkaline phases were then acidified with hydrochloric acid, extracted with ether, washed and evaporated to dryness. There was obtained the hydroxylactone IIB which crystallized from ether after a few days, melting point 230 C. For analysis, the product was recrystallized from a mixture of acetone and ether, melting point 232 C., specific rotation Compound 2013,18-lactone of 30:, 20a,20,3, trihydroxy-Sfipregnane-ll-one-lB-oic acid, IIB was obtained in the form of colorless needles which were soluble in alcohol, acetone and dilute aqueous alkalis, very slightly soluble in ether and chloroform and insoluble in water and dilute aqueous acids.

Analysis. C H O =362.45. C a l c u l a t c d: C, 69.58%; H, 8.34%. Found: C, 69.8%; H, 8.3%.

The infra-red spectrum indicates the existence of a hydroxyl group, an unconjugated ketone group and a lactone group, and confirms the hydroxylactone IIB struc' ture of the product obtained thereby.

(b) The 18,11-lact0ne of 3a1J, 3,20fl-trihydr0xy-5flpregnane-18-0ic acid, lIl.-l.04 gm. of the hydroxylactone of the formula 20 3, l8-lactone of 3oz,20oz,20;3, trihydoxy-Sfirpregnane-l1-one-18-oic acid, IIB, melting point 230, were introduced into 21 cc. ethanol containing 20% water, 1.04 gm. of potassium borohydride were added and the mixture was refluxed for four hours. Thereafter the reaction mixture was acidified with hydrochloric acid to pH 1, 40 cc. water were added and the mixture was vacuum filtered. The filter cake was washed with water and with acetone and after drying yielded compound 18,11-lactone of 3a,11fl,20B-trihydroxy-5 3- pregnane-lS-oic acid, III, melting point about 310 C., specific rotation [c] =+54il0 (c.=0.16% ethanol). It was very slightly soluble in alcohol, ether, acetone, benzene and chloroform, and insoluble in water and dilute aqueous acids or alkalis; it is obtained in the form of hexagonal crystals.

Analysis.C H O =348.47. Calculated: C, 72.38%; H, 9.26%. Found: C, 72.4%; H, 9.2%.

The infra-red spectrum confirms the existence of a lactone and a hydroxyl group.

' The product is not described in the literature.

(0) The 18,11-lactone of 1JB-hydrOxy-Sfl-pregrtane-S, ZO-dione-18-0ic acid, I V.-1.65 gm. of lactone, the 18,11- lactone of 304,1113,ZOB-trihydnroxy-SB-pregnane-18-oic acid, III were admixed with 16 cc. methylene chloride, 16 cc. acetic acid and 16 cc. of a 9.4% chromic acid solution in acetic acid. The mixture was agitated at room temperature for a few minutes. During this time dissolution took place and then a gummy precipitate was formed which was redissolved by adding 6.6 cc. water. After agitating for one hour, 16 cc. methanol were added. The solution was concentrated in vacuo, and then 60 cc. water were added. The mixture was vacuum filtered. The filter cake was washed with water and dried at 100 C. Product 18,11-lactone of llfl-hydroxy-SB-pregnane- 3,20-dione-18-ioc acid, IV was recovered, melting point 242 C., which was directly usable in the subsequent stage of the synthesis. For analysis, the product was recrystallized from a mixture of methylene chloride and ether, melting point 246 C., specific rotation [a] =-|55i5 (c.=0.5%, chloroform). The product was obtained in the form of large colorless plates which are soluble in alcohol, acetone, benzene and chloroform, very slightly soluble in ether and insoluble in water and dilute aqueous acids or alkalis.

Analysis.C H O =344.44. Calculated: C, 73.22%; H, 8.19%. Found: C, 73.4%; H, 8.2%.

The infra-red spectrum indicates the presence of two non-conjugated ketone groups and one 'y-lactone group.

This product is not described in the literature.

(d) The 18,11-lact0ne of 45-br0m0-11fl-hydroxy-5flpregnane-3,20-dione-18-0ic acid, V.680 mg. of the 18,11-lactone of 11/8-hydroxy-5B-pregnane-3,20-dione-18- oic acid, IV, were admixed with 6.8 cc. dimethyl formamide containing one drop of a 35% solution of hydrobromic acid in acetic acid. Thereafter, the mixture was brorninated at a temperature of 40 C. with 3.8 cc. of 10% solution of bromine in acetic acid. After fifteen minutes, the reaction mixture was poured into water and the aqueous mixture was extracted with methylene chloride. The extract solutions were washed with water, dried and evaporated to dryness. The residue, consisting of compound 18,11-lactone of 4-bromo-11B-hydroxyp-pregnane-3,20dione-18-oic acid, V, crystallized from a mixture of ethyl acetate and ether (4:6), melting point 220 to 230 C.

Recrystallization from a mixture of acetone and ether yielded a sample of the pure product, melting point 220 to 230 C., specific rotation [a] =+67i5 (c.=0.5%, chloroform). It was obtained in the form of hexagonal crystals which are soluble in acetone and chloroform, slightly soluble in alcohol and somewhat less soluble in ether, and insoluble in water and dilute aqueous acids or alkalis.

Analysis.-C H O Br 423.35. 59.57%; H, 6.43%; O, 15.12%; Br, 18.9%. C, 59.3%; H, 6.3%; O, 15.1%; Br, 19.3%.

Calculated: C, Found:

The infra-red spectrum shows the presence of a *ylactoue group, a non-conjugated ketone function and a ketone group with an equatorial bromine on the carbon atom adjacent to the ketone group or in the a-position.

This product is not described in the literature.

(e) The 18,]1-lact0ne of 1lfi-hydroxy-n -pregnene-3, 20-di0ne-18-0ic acid, Vb-300 mg. of dry lithium oarbonate, mg. of anhydrous lithium bromide and 10 cc. dimethyl formamide were admixed. About 2 cc. of the solvent were distilled off. Then 300 mg. of the 18,11- lactone of 4&bromo-1lfi-hydroxy-Sfi-pregnane-Ii,20-dione- 18-oic acid, V, were introduced into the mixture. The mixture was boiled for twenty minutes while distilling off 3 cc. The solution was then cooled, 25 cc. water were added. Then an excess of acetic acid was added, and the mixture was extracted with methylene chloride. The extract solutions, after washing with water and drying, were evaporated to dryness. Compound 18,11-lactone of l-lfl-hydroxy-A -pregnene-3,20-dione-18-oic acid, VI was obtained which was crystallized from a mixture of ethyl acetate and ether (4:6), melting point 173 C. By recrystallization from a mixture of acetone and ether a product was obtained which melts at 174 C., specific rotation [oc] =+l67i5 (c.=0.5%, chloroform). The star-like crystals of Compound VI were soluble in alcohol, acetone and chloroform, very slightly soluble in ether and insoluble in water and dilute aqueous acids or alkalis.

Analysis.-C H O =342.42. Calculated: C, 73.66%; H, 7.66%; 0, 18.69%. Found: C, 73.5%; H, 7.5%; O, 19.1%.

The infra-red spectrum shows the presence of a 7- lactone group, a non-conjugated ketone group and a conjugated ketone group.

While we have set forth specific examples and preferred modes of practice of our invention, it will be understood that the invention is not limited to the embodiments of operation described above. More particularly, it is possible to employ equivalent techniques known to those skilled in the art, and to make various changes and modifications without departing from the spirit of the disclosure or the scope of the appended claims.

We claim:

1. A process for the preparation of the 18,11-1actone of 11fl-hydroxy-A -pregnene-3,20-dione-18-oic acid comprising the steps of oxidizing 3a-acetoxy-18,20fl-oxido-5fipregnane-11-one with a sulfochromic mixture, treating said oxidized product with an alkali metal hydroxide to obtain 3u-hydroxy-5fl-pregnane-11,20-dione-l8-oic acid, isolating said acid in the form of the hydroxy lactone isomer 2018,18-lactone of 3a,20a,20fl,trihoxy-5B-pregnane-11-one-18-oic acid, IIB, reducing said lactone to the 18,11-lactone of 3a,1 113,20fi-trihydroxy-SB-pregnane-18- oic acid with an alkali metal boron hydride, oxidizing the hydroxyl groups in the 3- and 20- positions with a chromic acid mixture to obtain the 18,1l-lactone of llfi-hydroxy- 5B-pregnane-3,20-dione-18-oic acid, and introducing a double bond in the 4,5 position, by brominating and dehydrobrominating said 18,11-lactone.

2. A process for the preparation of 18,11-lactone of 1IB-hydroxy-M-pregnene-S,20-dione-1-8-oic acid comprising the steps of oxidizing 3oc-acetoxy-l8,20fl-oxido-5flpregnane-ll-one with a mixture of chromic acid anhydride and sulfuric acid in an inert organic solvent, treating said oxidized product with sodium hydroxide to obtain 3ahydroxy-5B-pregnane-11,20-dione-18-oic acid, isolating said acid in the form of the hydroxy lactone 20,9,18-lactone of 3a,20a,20fl,trihydroxy-5,8-pregnane-11- one-18-oic acid, IIB, reducing said lactone to the 18,11- lactone of 3a,11,6,20;8-trihydroxy-5p-pregnane-18-oic acid with potassium borohydride in an inert organic solvent, oxidizing the hydroxyl groups in the 3- and 20- positions with chromic acid anhydride in acetic acid to obtain the 18,11-lactone of 11fi'hydroxy-5fl-pregnane-3,20-dione-18- oic acid, and introducing a double bond in the 4,5 position by brorninating and dehydrobrominating the said 18,11- lactone.

3. The 18,11-lactone of 304,11fl-ZOfl-trihydroxy-Sfl-pregnane-18-oic acid.

4. A compound having the formulai OOOH 5. A compound having the formula:

H References Ciied in the file of this patent FOREIGN PATENTS 15 560,499 Canada July 22, 1958 OTHER REFERENCES Heusler et a1.: Experientia, vol. 16, No. 1 (1960), pp. 21-24.

Djerassi: Optical Rotary Dispersion, 1960, McGraw- Hill Book Co., Inc, New York, pp. 1-293. 

1. A PROCESS FOR THE PREPARATION OF THE 18,11-LACTONE OF 11B-HYDROXY-$4-PREGNENE-3,20-DIONE-18-OIC ACID COMPRISING THE STEPS OF OXIDIZING 3A-ACETOXY-18,20B-OXIDO-5BPREGENE-11-ONE WITH A SULFOCHROMIC MIXTURE, TREATING SAID OXIXIZED PRODUCT WITH AN ALKALI METAL HYDROXIDE TO OBTAIN 3A-HYDROXY-5B-PREGNENE-11,20-DIONE-18-OIC ACID ISOLATING SAID ACID IN THE FORM OF THE HYDROXY LACTRONE ISOMER 20B,18-LACTONE OF 3A,20A,20B, TRIHOXY-5B-PREGNANE-11-ONE-18-OIC ACID, IIB, REDUCING SAID LACTONE OF THE 18,11-LACTONE OF 3A,11B,20B-TRIHYDROXY-KB-PREGNENE-18OIC ACID WITH AN ALKALI METAL BORON HYDRIDE, OXIDIZING THE HYDROXYL GROUPS IN THE 3- AND 20- POSITIONS WITH A CHROMIS ACID MIXTURE TO OBTAIN THE 18,11-LACTONE OF 11B-HYDROXY5B-PREGNENE-3,30-DIONE- 18-OIC ACID, AND INTRODUCING A DOUBLE BOND IN THE 4,5 POSITION, BY BROMINATING AND DEHYDROBROMINATING SAID 18,11- LACTONE. 